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Cancer stem cell:

Cancer stem cell Swapnarani Nayak Swapnarani.nayak@rediffmail.com

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Cancer stem cells Rare cells within tumors with the ability to self-renew and give rise to the phenotypically diverse tumor cell population to drive tumorigenesis Normal stem cells Rare cells within organs with the ability to self-renew and give rise to all types of cells within the organ to drive organogenesis

Properties shared by normal stem cells and cancer stem cells:

Properties shared by normal stem cells and cancer stem cells Assymetric Division: Self renewal Tissue-specific normal stem cells must self-renew throughout the lifetime of the animal to maintain specific organs Cancer stem cells undergo self-renewal to maintain tumor growth Differentiation into phenotypically diverse mature cell types Give rise to a heterogeneous population of cells that compose the organ or the tumor but lack the ability for unlimited proliferation (hierarchical arrangement of cells) Regulated by similar pathways Pathways that regulate self-renewal in normal stem cells are dys -regulated in cancer stem cells

Two General Models for Cancer Heterogeneity:

Two General Models for Cancer Heterogeneity 1. All cancer cells are potential cancer stem cells but have a low probability of proliferation . 2. Only a small definable subset of cancer cells are cancer stem cells that have the ability to proliferate indefinitely.

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Self renewal and differentiation are random. All cells have equal but low probability of extensive proliferation. Only cells with self renewal capacity can sustain tumor growth. Distinct classes of cells exist within a tumor. Only a small definable subset, the cancer stem cells can initiate tumor growth.

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Human hematopoietic cells are organized in a hierarchy that is sustained by a small population of self-renewing hematopoietic stem cells (HSCs). HSCs give rise to progressively more lineage-restricted, differentiated progenitors with reduced self-renewal capacity (LTC-ICs, long-term culture-initiating cells; CFU, colony-forming units), which in turn produce functionally mature blood cells. Disruption of pathways regulating self-renewal and differentiation through the acquisition of transforming mutations generates leukemic stem cells (LSCs) capable of sustaining growth of the leukemic clone in vivo . LSCs possess an altered differentiation program, as demonstrated by aberrant expression of some cell-surface markers (indicated in blue) and give rise to an aberrant developmental hierarchy that retains aspects of its normal counterpart. In vivo reconstitution assays using immune-deficient mouse recipients enable detection of HSCs and LSCs as SCID-repopulating cells (SRCs) and SCID leukemia-initiating cells (SL-ICs), respectively. Hierarchies in normal and leukemic human hematopoietic cells Wang and Dick 2005 Trends in Cell Biology 15:494-501

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Self-renewal is a key property of both normal and leukemic stem cells. Fewer mutagenic changes are required to transform stem cells in which the self-renewal machinery is already active (a) , as compared with committed progenitors in which self-renewal must be activated ectopically (b) . In addition, self-renewing stem cells are long-lived; thus, there is an increased chance for genetic changes to accumulate in individual stem cells in comparison with more mature, short-lived progenitors. If a committed progenitor with limited life span acquires a genetic mutation that does not confer increased self-renewal (c) , that cell will likely die or undergo terminal differentiation before enough mutations occur to propagate a full leukemogenic program. The importance of self-renewal in leukemic initiation and progression.

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FUTURE DIRECTIONS Need to characterize cancer stem cells at the single cell level Understand the genetic and biochemical mechanisms that control the self-renewal phenotype, assymetric subdivision, and the role of the stem cell niche in regulating the biological properties of both normal and cancer stem cells. Characterize the response of cancer stem cells to chemotherapeutic regimens Develop therapeutic strategies to target cancer stem cells to prevent tumor recurrence.

Metastasis:

Metastasis Process by which a tumor cell leaves the primary tumor, travel to a distant site via the circulatory system and then establishes a secondary tumor. Final and most devastating step of a malignancy Leading cause of death in cancer patients Before mets tumors may be cured by surgery

Metastasis is a multi-step process Metastatic cell = “Decathlon champion” Vascularization of primary tumor Tumor grows through the synthesis and secretion of pro-angiogenic factors by the tumor and surrounding stroma Invasion of the organ stroma through enhanced expression of enzymes (MMP9) Invasion of the lymphatic or vascular channels (may grow in these places) Tumors cells enter circulation Must survive turbulence of circulation and evade both immune and non-immune mechanisms

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Summary: The Metastatic Process

FUTURE DIRECTIONS:

FUTURE DIRECTIONS Understand the factors and mechanisms that lead to metastasis rather than study metastatic end points What steps of metastasis provides good therapeutic targets? Are the early steps clinically detectable and is the process a good biological target? Understand the “cross-talk’ between metastatic cells and target organs that establish metastases What are the “messages” What are the “messengers” Target the soil to prevent the growth of the seed Develop therapies to alleviate metastases while minimizing therapies that will subject the patient to unnecessary toxicities